Centrally penetrant cannabanoid-1 receptor (CB1) inverse agonist compounds are efficacious for weight loss, glycemic control and treatment of cardiovascular risk factors associated with obesity and/or Type II diabetes mellitus. However such compounds are also associated serious adverse effects such as anxiety, depression, suicidal ideation, and others, which adverse effects preclude their use. Peripherally restricted cannabanoid-1 receptor (CB1R) inverse agonists aim to selectively inhibit the CB1R in organs/tissues outside the blood-brain barrier, for example in the liver, adipose tissue and/skeletal muscle, to avoid the adverse effects. Thus, there remains a need for peripherally restricted cannabanoid-1 receptor (CB1R) inverse agonists for the treatment of, for example metabolic disorders, such as obesity, Type II diabetes mellitus, and Syndrome X.
The compounds of this invention are peripherally restricted CB1R inverse agonists and represent novel therapeutic agents for the treatment of metabolic disorders such as obesity and Type II diabetes. PEGylation (covalent attachment of a polyethylene glycol polymer) has been used to improve the bioavailability and ease of formulation of small molecule drugs having poor aqueous solubilities. PEGylation may confer beneficial properties on protein, peptide, and small molecule drugs, including extended in vivo half-life, enhanced aqueous solubility, reduced immunogenicity of peptides and proteins, and potentially limited brain penetration.
Thus, PEGylated CB-1 inverse agonists of the present invention may provide therapeutic benefit for the treatment of metabolic disorders such as obesity, Type II diabetes mellitus, and Syndrome X without the adverse effects associated with antagonism of the CB-1 receptor.
PEGylation of small molecule drugs, however, poses distinct challenges. In particular, identification of permissive sites on the small molecule to which the PEG polymer may be attached without loss of biological activity can be difficult. In addition, the high molecular weight (10-40 kDa) and polydisperse nature (range of molecular weights) of commercially available PEGs makes the development of sensitive and robust methods for analysis of the PEG-small molecule conjugate extremely problematic.
To address the problems associated with bioanalysis of PEG-small molecule conjugates, the present invention also includes a linker that is stable in vivo but permits quantitative liberation of a discrete small molecule from the PEG polymer under orthogonal chemical cleavage conditions ex vivo. The small molecule can be analyzed and quantified using conventional methods such as mass spectrometry. The utility of cleavable linker technology in chemical biology has been recently reviewed (Bioorganic and Medicinal Chemistry 20 (2012) 571-582).